Pharmaceutical composition for the treatment of malignant neoplasms and immunosuppressive deficiencies and its method of production

ABSTRACT

A pharmaceutical composition for the treatment of malignant neoplasms and immunosuppressive deficiencies and its method of production, the active ingredients of said composition being DL-kinurenine associated with thymine.

This application is a 371 of PCT/BR 98/00045 which has a filing date ofJun. 29, 1998.

FIELD OF THE INVENTION

The present invention refers to a pharmaceutical composition for thetreatment of malignant neoplasms and immunosuppressive deficiencies, byre-establishing the biochemical balance within the cells, mainly thosecells undergoing a disordered reproduction, and to a method forproducing said pharmaceutical composition.

BACKGROUND OF THE INVENTION

Nowadays, the existence of several types of cancer control by means ofconventional treatments has conducted, after studies based on cellularbiochemistry, to the provision of a pharmaceutical composition formed byan essential aminoacid of the benzoic genesis and by a geneticderivative of a pyrimidinic nitrogenized base. The experiment hasclinically proved its efficiency on the neoplastic cells, avoiding theirdisordered reproduction.

DISCLOSURE OF THE INVENTION

Thus, it is a first objective of the present invention to use theefficiency of the active ingredients of an essential aminoacid of thebenzoic genesis with a pyrimidinic nitrogenized base in a biologicallyacceptable pharmaceutical formula in the following compositions:DL-kinurenine, [2-amine-3-(2-aminebenzene)propionic acid] and tymine,[2,1 dihydroxy-5-methyl-pyrimidine;5-methyluracil].

A further objective of the present invention is to provide a method forproducing a pharmaceutical composition, which is formulated for thedissolution of 1.5-6.0 grams, preferably 3-4 grams of DL-kinurenine and1.2-7.0 grams, preferably 2.5-3.5 grams of tymine in 50 ml of distilledwater, preferably at about 50° C., resulting in a stabilized solutionwith a neutral pH of about 5.6 to 9.0, preferably from 6.8 to 7.3 byadding an adequate amount of potassium or sodium hydroxide.

Taking into account that DL-kinurenine is the final product of anthraniltransformation in the biochemical reactions, in which is includedtryptophan, which precedes kinurenine, it has been verified that it ispossible to substitute kinurenine by tryptophan in the desiredpharmaceutical composition, without modifying the effects. Tryptophan[(R)-2-amine-3-(indole-propionic acid) associated with tymine has becomeviable for the pharmaceutical composition in the originally suggestedproportions.

The substances mentioned in the described pharmaceutical compositionhave their active ingredients diluted in distilled water or in the formof encapsulated powder and are intended for oral administration. Theyresult in a new drug for treating the biochemical disorders found in allneoplastic cells and with immunosuppressive deficiencies.

The observation of the biochemical reactions that occur within thecells, in terms of DNA and RNA, between the aminoacids and the functionsof the nitrogenized bases in the presence of the enzymatic systems, hasallowed the correction of several forms of lesions in the chromossomalstructures caused by hydrolysis or external mutagenic agents,deaminating agents and alkylating agents (Ames, 1979,204:587-593;Cairns, 1975,233:64-78; and Goodman and Gilman, 1987). It has beendeveloped a pharmaceutical formulation, obtaining a product formed bythe association of an aminoacid of the benzoic genesis with apyrimidinic nitrogenized base which, inside the cell, in terms of DNAand RNA in the presence of carboxylase, produces a double effect, i.e.,neutralizes the formylic radicals which appear during the irregularmitosis of the chromosomal structures and eliminates the energy producedwith oxygen release for the formation of the neoplastic cells.

This process, called catacholase, stops the liberation of energy byoxygen and completes the neutralization of the formylic radicals,re-establishing the bridge with the deoxyribonucleoside of the DNAchromosomes (Lawitscka, Dados Informativos de Pesquisa (ResearchInformative Data), 1960). The neoplastic cells during the cellularmitosis have a defect in the ribonucleosidase of the purines. Failure inthis purine formation makes the cell become cancerous.

Knowing that the nucleic acids are informative molecules which controlthe basic processes of the cellular metabolism, the synthesis of themacromolecules, the cellular differentiation and the transmission of thegenetic inheritance, this new product has been induced to act directlyin the interior of the cell (Valeriote and Santelli, 1984, 107-132).

The present product is found in both powder and liquid forms. As apowder, it is encapsulated with an innocuous vehicle, while in theliquid form it is an aqueous solution stabilized with a neutral pH.

The product consists essentially of DL-kinurenine aminoacid associatedwith the pyrimidinic nitrogenized base, tymine, and may be produced as apowder or liquid pharmaceutical formulation.

The maximum dose which is recommended to obtain the desired effect overthe neoplastic cells is 275 mg/day of DL-kinurenine and 250 mg/day oftymine, in a pharmaceutical formulation which is orally administeredeach 8 hours, the serous level being maintained with no toxicity of theactive ingredients of the components. Efficiency in a treatment ofmalignant neoplasms is achieved with the recommended dose of 100-1,500mg/day of DL-kinurenine and 100-1,400 mg/day of tymine.

The product in question is indicated for malignant neoplasms andimmunosuppressive deficiencies as a cellular restorer. It may be addedin powder form to a nutritional supplement, when indicated in the dietsof patients convalescing from surgeries of cancerous tumor removal andin the immunological deficiencies. It is innocuous, does not havecontraindications and does not cause side effects and adverse reactionswhen properly used. The validity period is 24 months from themanufacture date, in which period no alterations were detected in thephysical-chemical characteristics of its active ingredients. Either incapsules or in the liquid form, the product should be kept away fromlight, heat and humidity and packaged in a plastic container for thecapsules or sachets, or in a dark glass container when in the liquidform.

The pharmaceutical composition of the drug named tk-3 comprises thefollowing components in the liquid form:

    ______________________________________                                        DL-kinurenine           3.3 g                                                   tymine  3.0 g                                                                 potassium hydroxide 0.63 g                                                    distilled water   50 ml                                                     ______________________________________                                    

In encapsulated powder or in sachets:

    ______________________________________                                               DL-kinurenine   3.3 g                                                    tymine  3.0 g                                                                 kaolin  187 g                                                               ______________________________________                                    

For the total amount of 250 mg corresponding to capsules of 500 mg ofthe active ingredients of the substances.

In clinical experiments, based on studies and observations of thebiochemical transformations of the active ingredient of the componentsof the pharmaceutical composition, it has been concluded thatDL-kinurenine may be replaced by tryptophan in the same proportion,without altering the desired result for the treatment of patients withmalignant neoplasms.

BEST MODE OF CARRYING OUT THE INVENTION

The knowledge of the chromosomal structures, DNA and RNA components, aswell as the related biochemical reactions has permitted the detection ofa defect in the ribonucleasidase of the purines. By using the essentialaminoacid resulting from the transformation of anthranil, 2-benzoicaminoacid, into tryptophan and finally into DL-kinurenine, which is thethird degree of the benzoic genesis of these aminoacids, associated witha pyrimidinic nitrogenized base, the tymine [2,4dihydroxy-5-methylpyrimidine;5-methyluracil], it has been detected acellular biochemical reaction taking place in the nucleosides andnucleotides of the neoplastic cells, by the enzymatic action ofcarboxylase. This biochemical reaction of the active ingredients of theproduct has the purpose of eliminating the energy produced by oxygenrelease and of neutralizing the nitrogen of the formylic radicalsproduced in the disordered cellular mitosis of the neoplastic cells. Inthis biochemical reaction of the cell, 5-methyluracil re-establishes thecellular genesis and DL-kinurenine eliminates the nitrogenized methylicand formylic radicals which appear during the cellular mitosis.5-methyluracil re-establishes the bridge with the deoxyribonucleoside,with the atypical chromosomes being eliminated, since they do not obeythe benzoic genesis of the cell (Lawitscka, Reseach Informative Data,1960-1980); (Jones, 1980,49:253-279); Fraile, 1980, 2223-2228; Valerioteand Santelli, 1984, 107-132 and Jones, 1979,98:1-8).

The nucleotides and nucleosides of the normal cells take the cell to amitosis, in which the chromosomes are multiplied in pairs and not as itoccurs in the neoplastic cell, in which the multiplication takes placein groups of four.

The four purinic nitrogenized bases of DNA and RNA (Adenine and Guanine,A and G) and pyrimidinic bases of DNA (Citosine and Tymine, C and T) andof RNA (Citosine and Uracil, C and U), which are components of thenucleic acids, form together with glucose (pentose) the first link forthe fusocellular mitosis, by action of ribonucleosidase, which effectsthe cellular mitotic genesis. A failure in this formation of the purinesmakes the cell become cancerous. A purine may be replaced by aribonucleoside, but not in the cellular mitosis. In the mitosis it isirreplaceable. The oxyribonuclease and deoxyribonuclease enzymes arepresent in the mitotic cellular genesis, transformed by carboxylase.Deoxyribonuclease is the carrier of the cellular genesis and allows thecommunication among the chromosomes by means of 5-methyluracil, whicheliminates the free oxygen by action of kinurenine over the formylicradicals, transforming in oxy-kinurenine formyl, neutralizing the energyof the cancerous cell. Once re-established the bridge with thedeoxyribonucleoside by the transformation of uracil into 5-methyluracil-in the presence of tryptophan, transformed into oxykinurenine formyl,the formylic and methylic nitrogenized radicals are eliminated, allowingthe cell to return to a normal mitosis (Lawitscka, Informative Data,1960).

It may be observed that it is possible, by administering the product inits liquid or powder forms, to correct several forms of DNA lesions,which make the cell become cancerous.

Adults may take a recommended daily dose of 275 mg of DL-kinurenine ortryptophan and 250 mg/day of tymine. The daily dose of kinurenine mayvary from 100 mg to 1,500 mg, the more indicated dose being 275 mg/day,as well as for tryptophan, and from 100 to 1,500 mg of tymine. Thesedoses are recommended for both the liquid and powder forms. The normalserous level of tryptophan is 11+-2 mg/l and an adult excretes 50 mg ofxanthurenic acid in the urine in 24 hours upon taking 2 g of tryptophanorally. Therefore, the indicated doses should not surpass therecommended limits. An overdose would cause pyridoxal deficiency andabnormal excretion of xanthurenic acid, resulting in pathologicalalterations, such as pyridoxine deficiency (vit. B6) and increase ofurinary indoles (Hughes, Raine, 1966:399; Guibaut and Froelich, 1973,112; Gehe=Mann, 1959, 1:165).

It should be noted that the present invention is not limited to theexamples or details contained herein. The results described above, whichhave been obtained by using the present composition, confirm that thisdrug is adequate for the treatment of neoplasms and immunosuppressivedeficiencies, the preparation of the composition being easily carriedout with commercially available raw materials.

What is claimed is:
 1. A method for producing a pharmaceuticalcomposition for the treatment of malignant neoplasms andimmunosuppressive deficiencies, which comprises the steps of dissolvingabout 1.2 to 7.0 grams of Thymine and about 1.5 to 6.0 grams ofDL-Kinurenine in 50 ml of distilled water at a temperature of about 50°C., and adding a base selected from potassium hydroxide or sodiumhydroxide, in order to obtain a stabilized solution with a pH from 6.5to 9.0.
 2. The method according to claim 1, wherein the pH is from 6.8to 7.3.
 3. The method as in claim 1 wherein about 2.5 to 3.5 grams ofThymine and about 3 to 4 grams of DL-Kinurenine are dissolved in 50 mlof distilled water at a temperature of about 50° C., and adding a baseselected from potassium hydroxide or sodium hydroxide, in order toobtain a stabilized solution with a pH from 6.8 to 7.3.
 4. The methodaccording to claim 3 wherein DL-Kinurenine is substituted by Tryptophan.5. A method for the treatment of malignant neoplasms andimmunosuppressive deficiencies in humans, which comprises: administeringto humans suffering from malignant neoplasms and immunosuppressivedeficiencies a stabilized solution having a basic pH containingtherapeutically effective amounts of Thymine and DL-Kinurenine.
 6. Themethod of treatment of claim 5 wherein the solution has a pH of about6.5 to 9.0 and contains from about 1.2 to 7.0 grams of Thymine and fromabout 1.5 to 6.0 grams of DL-Kinurenine in 50 ml of distilled water. 7.The method of treatment of claim 6 wherein the solution has a pH ofabout 6.8 to 7.3 and contains about 2.5 to 3.5 grams of Thymine and fromabout 3 to 4 grams of DL-Kinurenine in 50 ml of distilled water.
 8. Themethod of treatment of claim 5 wherein Tryptophan is substituted forDL-Kinurenine.
 9. The method of treatment of claim 6, wherein Tryptophanis substituted for DL-Kinurenine.
 10. The method of treatment of claim7, wherein Tryptophan is substituted for DL-Kinurenine.